Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, members of which exert prompt stimulatory action on smooth muscle tissue. Substance P is a pharmaceutical active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is illustrated in U.S. Pat. No. 4,680,283. A variety of substance P antagonists could be prepared from the title compound; for example, U.S. Pat. No. 5,162,339 describes Substance P antagonists of formula 2 where R1 is methoxy and R2 is independently selected from the group consisting of isopropyl, tert-butyl, methyl, ethyl, and sec-butyl. 
These substance P antagonists can be prepared by the reductive amination of cis-2-benzhydryl-3-amino-quinuclidine 1 using the appropriate aldehyde of the formula R3CHO where R3 is defined as a benzaldehyde derivative with the phenyl ring substituted with R1 and R2 as described above, This reductive amination may be achieved with a variety of reagents such as hydrogen in the presence of a suitable metal catalyst, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, zinc and hydrochloric acid, borane dimethylsulfide or formic acid as described, for example, in WO92/21677, WO94/10170, WO94/11368, WO94/26740, WO94/08997WO97/03984, and U.S. Pat. Nos. 5,162,339, 5,721,255, 5,939,433, and 5,939,434. An alternative strategy is the conversion of 1 to 2 by an alkylation with an appropriate electrophile as is taught, for example, in U.S. Pat. Nos. 5,807,867 and 5,939,433 and WO92/21677. A further alternative strategy for the conversions of 1 to 2 is the acylation of 1 with an activated carboxylic acid derivative followed by reduction of the resultant amide with a reagent such as lithium aluminum hydride as described in WO92/21677 and the Journal of Medicinal Chemistry, 35, 2591 (1992).
The cis-2-benzhydryl-3-amino-quinuclidine 1, which is an intermediate in the formation of 2, is available from the 3-benzylamine-2-benzhydryl-quinuclidine 4 by debenzylation with hydrogen gas and a catalyst. A process for preparing benzylamine 4 has been described by Warawa in the Journal of Medicinal Chemistry, 18, 587 (1975) and is illustrated in Scheme 1. The process starts with 3-quinuclidinone 5, available by the method of Clemo et al in the Journal of the Chemical Society (London) p1241 (1939), which is condensed with benzaldehyde to generate enone 6. In turn, this is reacted with phenylmagnesium chloride to form 2-benzhydryl-3-quinuclidinbne 3. Reductive alkylation of ketone 3 with benzylamine provides 4. 
The approach is amenable to adaptation to allow access to aryl and quinuclidine analogs as described in WO92/20676 and U.S. Pat. No. 5,162,339. The use of methoxybenzylamine has been used in place of benzylamine as this allows for hydrolytic removal to afford the amine 1 as well as hydrogenolysis, as described in U.S. Pat. Nos. 5,807,867 and 5,939,433.
The use of 9-BBN to effect the imine reduction formed from the reaction of benzylamine with the ketone 3 has been advocated as this maximizes formation of the desired cis-isomer of 4. This procedure is described in the Journal of Medicinal Chemistry, 35, 2591 (1992).
In all of these examples, the materials were racemic. The separation of enantiomers has been done on compound 1, 2, or 4 by classical resolution techniques. This is illustrated by the methodology described, for example, in U.S. Pat. No. 5,138,060, where the methoxyphenyl derivative 7 is separated to provide the desired (−)-isomer by crystallization of racemic 7 with (−)-mandelic acid from ethyl acetate, purification of the salt by subsequent recrystallization from ethyl acetate, and release of, the free amine product by treatment with base. In a related procedure, N-[[2-methoxy-5-(1-methylethyl)phenyl]methyl]-2-(diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-amine is resolved by use of (1R)-(−)-10-camphorsulfonic acid, as described in WO 97/03984. 
Use of D-tartaric acid has been disclosed in Japanese Patent No. 07025874 by Murakami, et al. for the resolution of cis-3-amino-2-benzhydrylquinuclidine (1) in methanol. Separation of the diastereoisomers of an intermediate carbamate have also been used to obtain 1 as a single enantiomer as described in the Journal of Medicinal Chemistry, 35, 2591 (1992).